Our research is focused on understanding the multistep process of tumorigenesis and the mechanisms that suppress tumor formation and progression. We have developed systems from genetically engineered mice to uncover and deconstruct the timing and mechanism of action for tumor suppressor genes commonly mutated in human cancers. Our work here focuses on a lung adenocarcinoma, a common malignancy associated with poor prognosis. Additionally, we focus on the p53 tumor suppressor as it is the most frequently mutated gene in this cancer type. We employ a strategy that allows the temporal control over p53 actions in established murine lung adenocarcinomas that allows us to determine the relevant biological programs that ensue upon p53 action in these cancers. We have identified a non-cancer cell autonomous program of tumor regression that requires natural killer cells. Our innovative strategy and unique in vivo and cell culture systems afford us the ability to interrogate the roles of specific molecules regulated by p53 in the cancer and the physiological response of natural killer cells as they mediate tumor regression. Our goal here is to mechanistically define this tumor suppressive pathway. These insights will be important for future work aimed at developing tumoricidal natural killer cells that could be used as a cell-based anti- cancer therapy.